CDHR3 gene variation and childhood bronchiolitis.
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ABSTRACT:
SUBMITTER: Husby A
PROVIDER: S-EPMC5675819 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
CDHR3 gene variation and childhood bronchiolitis.
Husby Anders A Pasanen Anu A Waage Johannes J Sevelsted Astrid A Hodemaekers Hennie H Janssen Riny R Karjalainen Minna K MK Stokholm Jakob J Chawes Bo L BL Korppi Matti M Wennergren Göran G Heinzmann Andrea A Bont Louis L Bisgaard Hans H Bønnelykke Klaus K
The Journal of allergy and clinical immunology 20170804 5
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Project description:BackgroundViral bronchiolitis is a common respiratory infection that often affects term, otherwise healthy infants. A small literature suggests maternal stress during pregnancy is associated with bronchiolitis. However, the association between maternal exposure to lifetime traumatic stress, including traumatic events occurring in childhood or throughout the life course, and bronchiolitis has not been studied previously.ObjectivesTo investigate the association between maternal exposure to total lifetime and childhood traumatic stress events and infant bronchiolitis.MethodsWe studied mother-infant dyads enrolled in a prospective prenatal cohort, recruited 2006-2011, and Tennessee Medicaid. During pregnancy, we assessed maternal lifetime exposure to types of traumatic events by questionnaire. We captured bronchiolitis diagnoses in term, non-low birthweight infants' first 12 months using linked Medicaid data. In separate models, we assessed the association of maternal lifetime traumatic events (0 to 20 types) and a subset of traumatic events that occurred during childhood (0 to 3: family violence, sexual, and physical abuse) and infant bronchiolitis using multivariable log-binomial models.ResultsOf 629 women, 85% were African American. The median count (interquartile range) of lifetime traumatic events was 3 (2, 5); 42% reported ≥1 childhood traumatic event. Among infants, 22% had a bronchiolitis diagnosis (0 to 2 lifetime traumatic events: 24%; 3 events: 20%; 4 to 5 events: 18%; 6 or more events: 24%). Total maternal lifetime traumatic events were not associated with bronchiolitis in multivariable analyses. For maternal childhood traumatic events, the risk of infant bronchiolitis increased with number of event types reported: adjusted Risk ratios were 1.12 (95% confidence interval [CI] 0.80, 1.59), 1.31 (95% CI 0.83, 2.07), and 2.65 (95% CI 1.45, 4.85) for 1, 2, and 3 events, respectively, vs none.ConclusionsInfants born to women reporting multiple types of childhood trauma were at higher risk for bronchiolitis. Further research is needed to explore intergenerational effects of traumatic experiences.
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Project description:BackgroundBronchiolitis is the leading cause of hospitalization in U.S. infants and a major risk factor for childhood asthma. Growing evidence supports clinical heterogeneity within bronchiolitis. We aimed to identify endotypes of infant bronchiolitis by integrating clinical, virus, and serum proteome data, and examine their relationships with asthma development.MethodsThis is a multicenter prospective cohort study of infants hospitalized for physician-diagnosis of bronchiolitis. We identified bronchiolitis endotypes by applying unsupervised machine learning (clustering) approaches to integrated clinical, virus (respiratory syncytial virus [RSV], rhinovirus [RV]), and serum proteome data measured at hospitalization. We then examined their longitudinal association with the risk for developing asthma by age 6 years.ResultsIn 140 infants hospitalized with bronchiolitis, we identified three endotypes: (1) clinicalatopic virusRV proteomeNFκB-dysregulated , (2) clinicalnon-atopic virusRSV/RV proteomeTNF-dysregulated , and (3) clinicalclassic virusRSV proteomeNFκB/TNF-regulated endotypes. Endotype 1 infants were characterized by high proportion of IgE sensitization and RV infection. These endotype 1 infants also had dysregulated NFκB pathways (FDR < 0.001) and significantly higher risks for developing asthma (53% vs. 22%; adjOR 4.04; 95% CI, 1.49-11.0; p = 0.006), compared with endotype 3 (clinically resembling "classic" bronchiolitis). Likewise, endotype 2 infants were characterized by low proportion of IgE sensitization and high proportion of RSV or RV infection. These endotype 2 infants had dysregulated tumor necrosis factor (TNF)-mediated signaling pathway (FDR <0.001) and significantly higher risks for developing asthma (44% vs. 22%; adjOR 2.71; 95% CI, 1.03-7.11, p = 0.04).ConclusionIn this multicenter cohort, integrated clustering of clinical, virus, and proteome data identified biologically distinct endotypes of bronchiolitis that have differential risks of asthma development.
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Project description:BackgroundBronchiolitis is the leading cause of infant hospitalization in U.S. and is associated with increased risk for childhood asthma. Immunoglobulin E (IgE) not only plays major roles in antiviral immune responses and atopic predisposition, but also offers a potential therapeutic target.ObjectiveWe aimed to identify phenotypes of infant bronchiolitis by using total IgE (tIgE) and virus data, to determine their association with asthma development, and examine their biological characteristics.MethodsIn a multicenter prospective cohort study of 1,016 infants (age <1 year) hospitalized for bronchiolitis, we applied clustering approaches to identify phenotypes by integrating tIgE and virus (respiratory syncytial virus [RSV], rhinovirus [RV]) data at hospitalization. We examined their longitudinal association with the risk of developing asthma by age 6 years and investigated their biological characteristics by integrating the upper airway mRNA and microRNA data in a subset (n=182).ResultsIn infants hospitalized for bronchiolitis, we identified 4 phenotypes: 1) tIgElowvirusRSV-high, 2) tIgElowvirusRSV-low/RV, 3) tIgEhighvirusRSV-high, and 4) tIgEhighvirusRSV-low/RV phenotypes. Compared to phenotype 1 infants (resembling "classic" bronchiolitis), phenotype 4 infants (tIgEhighvirusRSV-low/RV) had a significantly higher risk for developing asthma (19% vs. 43%; adjOR, 2.93; 95% CI, 1.02-8.43; P=.046). Phenotypes 3 and 4 (tIgEhigh) had depleted type I interferon and enriched antigen presentation pathways; phenotype 4 also had depleted airway epithelium structure pathways.ConclusionsIn this multicenter cohort, tIgE-virus clustering identified distinct phenotypes of infant bronchiolitis with differential risks of asthma development and unique biological characteristics.
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Project description:BackgroundInfants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition.ObjectivesWe sought to identify biologically distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine the longitudinal relationships of metabotypes with asthma development.MethodsIn a multicenter prospective cohort study of infants (age, <12 months) hospitalized for bronchiolitis, the nasopharyngeal airway metabolome was profiled at hospitalization. Using a clustering approach, this study identified mutually exclusive metabotypes. This study also examined their longitudinal association with the risk of developing asthma by 5 years of age.ResultsOf 918 infants hospitalized for bronchiolitis (median age, 3 months), this study identified 5 distinct metabotypes-characterized by their nasopharyngeal metabolome profile: A, glycerophosphocholine-high; B, amino acid-high, polyunsaturated fatty acid-low; C, amino acid-high, glycerophospholipid-low; D, glycerophospholipid-high; and E, mixed. Compared with infants with metabotype A (who clinically resembled "classic" bronchiolitis), infants with metabotype B had a significantly higher risk for developing asthma (23% vs 41%; adjusted odds ratio, 2.22; 95% CI, 1.07-4.69). The pathway analysis showed that metabotype B had enriched amino acid (eg, methionine, histidine, glutathione) and α-linolenic/linoleic acid metabolism pathways (false discovery rate, <5 × 10-14 for all). Finally, the transcriptome analysis revealed that infants with metabotype B had upregulated IFN-α and IL-6/JAK/STAT3 pathways and downregulated fatty acid metabolism pathways (false discovery rate, <0.05 for both).ConclusionsIn this multicenter prospective cohort study of infants with severe bronchiolitis, the clustering analysis of metabolome data identified biologically distinct metabotypes, including a metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids that is at significantly increased risk for developing asthma.
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Project description:BackgroundYoung children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk.ObjectiveWe aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk.MethodsAs part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years.ResultsOf 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusRV-CmicrobiomemixedT2low; endotype B, virusRV-AmicrobiomeHaemophilusT2low; endotype C, virusRSV/RVmicrobiomeStreptococcusT2low; and endotype D, virusRV-CmicrobiomeMoraxellaT2high. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03).ConclusionsIntegrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.
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Project description:BackgroundWe sought to identify predictors of asthma development following severe early childhood RSV bronchiolitis. Different definitions of asthma were also compared.MethodsThis longitudinal, observational study (N = 343) followed patients (<2 years old) from a placebo-controlled trial (N = 979) of montelukast after RSV bronchiolitis to identify clinical, demographic, or biochemical predictors of asthma, atopic disorders, and chronic asthma therapy use at 6 years of age (Clinical Trials Registry Number: NCT01140048). Asthma (primary definition) was based on parental identification of wheeze at 6 AND 12 months before 6 years of age; definitions based on physician diagnosis as well as parental identification of wheeze at 6 OR 12 months (to consider seasonal effect) were also assessed. Post-hoc analyses evaluated agreement among asthma diagnosis criteria.ResultsPrevalence of asthma (primary definition by parental identification), asthma (physician diagnosis), atopic disorders, and chronic asthma therapy use (parental identification) was 6.1%, 22.4%, 36.2%, and 14.5%, respectively. Predictors for asthma (primary definition) included male gender, a relative with asthma, and RAST positive for dog dander; for physician diagnosis of asthma, high severity score for RSV bronchiolitis, high respiratory rate, and asthma diagnosis before enrollment. Predictors of atopic disorders included allergic rhinitis before enrollment, a relative with asthma, and the plasma biomarkers IL-5, IL-16, and IL-18. Predictors of chronic asthma therapy use included asthma diagnosis before enrollment and geographic region (Europe and Africa). Only 42% of patients with asthma (primary definition) also met the asthma definition by physician diagnosis and chronic asthma therapy use.ConclusionAmong children with early RSV bronchiolitis, hereditary factors (i.e., having a relative with asthma) and RSV bronchiolitis severity were predictors of asthma and atopic disorders at 6 years of age. Of interest, there was poor agreement among the asthma definitions evaluated. Pediatr Pulmonol. 2016;51:1382-1392. © 2016 Wiley Periodicals, Inc.
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